Lecture 16 Immune System The Price of

Lecture 16 Immune System

The Price of Affluence § Our bodies provide our cells with a: § Safe § Nutrient-rich § Temperature & p. H optimized environment. § This is quite attractive to other organisms that do not belong to our body § Many of these provide value and help maintain the environment by: § Breaking down macromolecules we can’t § Synthesizing needed nutrients § Keeping harmful organisms in check

There Are Some Bad Apples § They destroy or degrade the environment by: § Competing for nutrients § Overloading the system with toxins § Taking over and destroying cell machinery § Killing body cells § These are the disease causing organisms our body must defend against

What Does the Enemy Look Like? § A wide range of organisms try to exploit our bodies:

How would you approach this problem? § First line of defense: Secure the Borders § Prevent a problem from occurring in the first place § Skin and mucosae prevent entry of microorganisms § Second line of defense: Mobilize Quickly to Block a Breach § Antimicrobial proteins, phagocytes, and other cells localize the invasion § Inflammation is the hallmark and most important mechanism § Repair of the border is the ultimate solution § Third line of defense: Hunt Down Successful Invaders § Profile the enemy (this takes time) § Catch, immobilize, & destroy invaders in the body fluids § Identify, destroy, & remove body cells already infected

The Players & Their Tools:

1 st Line of Defense: Secure the Borders Skin, mucous membranes, and their secretions create a barrier § Keratin in the skin: § Presents a formidable physical barrier to most microorganisms § Is resistant to weak acids and bases, bacterial enzymes, and toxins § Mucosae provide similar mechanical barriers § Mucus-coated hairs in the nose trap inhaled particles § Mucosa of the upper respiratory tract is ciliated § Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages § Epithelial membranes produce protective chemicals that destroy microorganisms § Skin acidity (p. H of 3 to 5) inhibits bacterial growth § Sebum (ear wax) contains chemicals toxic to bacteria § Stomach mucosae secrete concentrated HCl and protein-digesting enzymes § Saliva and lacrimal fluid contain lysozyme § Mucus traps microorganisms that enter the digestive and respiratory systems

2 nd Line of Defense: Mobilize Quickly § The body uses nonspecific cellular and chemical devices to protect itself § Phagocytes and natural killer (NK) cells § Antimicrobial proteins in blood and tissue fluid § Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals § Harmful substances are identified by surface carbohydrates unique to infectious organisms

Phagocytes: Police the Fluid Areas § Macrophages are the chief phagocytic cells § Free macrophages wander throughout a region in search of cellular debris § Kupffer cells (liver) and microglia (brain) are fixed macrophages § Neutrophils become phagocytic when encountering infectious material § Eosinophils are weakly phagocytic against parasitic worms § Mast cells bind and ingest a wide range of bacteria

Natural Killer (NK) Cells: Look for Infected Cells § NK cells can lyse and kill cancer cells and virus-infected cells § Natural killer cells: § React nonspecifically and eliminate cancerous and virus-infected cells § Kill their target cells by releasing perforins and other cytolytic chemicals § Secrete potent chemicals that enhance the inflammatory response

Proteins Used To Kill Invading Microbes: Complement § Complement system § ~ 20 different proteins that separately are inactive § Aggregate to form a Membrane Attack Complex (MAC) § Kills invading microbes by forming holes in the cell membrane § Amplifies all aspects of the inflammatory response § Our cells are immune to complement § Is a major mechanism for destroying foreign substances in the body

Proteins That Warn Neighbors of Invading Microbes: Interferon (IFN) § Genes that synthesize IFN are activated when a host cell is invaded by a virus § Interferon molecules leave the infected cell and enter neighboring cells § Interferon stimulates the neighboring cells to activate genes for an antiviral protein (PKR) § PKR nonspecifically blocks viral reproduction in the neighboring cell § FDA-approved alpha IFN is used: § As an antiviral drug against hepatitis C virus § To treat genital warts caused by the herpes virus

The Inflammatory Response § The inflammatory response is triggered whenever body tissues are injured § Prevents the spread of damaging agents to nearby tissues § Disposes of cell debris and pathogens § Sets the stage for repair processes § Can be broken down into three stages 1. Injured tissue, phagocytes, lymphocytes, and mast cells release histamine and prostaglandins 2. These chemicals cause blood vessels to expand become more permeable causing redness and swelling 3. Neutrophils, then monocytes & macrophages migrate to the site of infection or injury § The four cardinal signs of acute inflammation are: 1. 2. 3. 4. Redness Heat Swelling Pain

Fever § Abnormally high body temperature in response to invading microorganisms § The body’s thermostat is reset upwards in response to pyrogens § These are chemicals secreted by leukocytes and macrophages when exposed to bacteria and other foreign substances § High fevers are dangerous as they can denature our own enzymes § Fevers are not used to directly kill invaders § Fevers greater than 40. 6 o. C (105 o. C) are often fatal § Moderate fever can be beneficial: § The primary benefit is an increase in the metabolic rate, which speeds up tissue repair § (1 o in temperature = 10 X metabolic increase) § It also causes the liver and spleen to sequester iron and zinc (needed by microorganisms), which may help slow infectious growth

3 rd Line of Defense: Attack Invaders § Acquired (or adaptive) immunity is a functional system that: § Recognizes specific foreign substances § Acts to immobilize, neutralize, or destroy them § Amplifies inflammatory response and activates complement § The adaptive immune system: § Is antigen-specific § An antigen is a molecule that provokes a specific immune response § Is systemic § It is not restricted to any region of the body § Has memory § Some “educated” cells remain after the invader is gone § It has two separate but overlapping arms § B cells: humoral immunity (body fluid) § T cells: cellular immunity § It is the most complex and slowest to respond § It has to activate cells for each new invader (antigen) § On first exposure it takes ~ 10 days to reach peak levels

B cells: Catching Invaders in the Body Fluids § Originate and mature in the bone marrow § To help you remember the name, you can think of the “B” as standing for where they mature in humans: Bone marrow § Circulate in blood and lymph § Proliferate upon antigen exposure into: § Plasma cells § That produce antibodies § Memory cells § That provide a quick response on re-exposure

T cells: Destroying Infected Cells § Originate in bone marrow and mature in the Thymus § Develop ability to identify foreign agents by antigens present on cell surfaces § Four main types of T cells § § Helper (TH) – Initiate the immune response (authorize the attack) Cytotoxic (TC) – Lyse virus-infected cells (licensed to kill) Memory (TM) – Provide a quick response on re-exposure (keep watch) Suppressor (TS) – Terminate the immune response (declare victory)

What is the 1 st Step in Identifying the Enemy? § Know Thy Self! § Every cell in the body carries surface markers called Major Histo. Compatibility (MHC) proteins § MHC proteins are different for each individual § So they act as “self” markers § Antigen-presenting cells § Ingest foreign particles and partially digest them § They combine pieces of the foreign particle with MHC proteins & move them to the surface of their cell membrane § T cell receptors can only interact with cells that have this combination of MHC and antigen

Initiating the Immune Response § Macrophages inspect the surface of cells looking for “self” MHC proteins § If a cell displays MHC protein-antigen (“self”/“nonself”) combinations the macrophage will secrete the protein interleukin-1 as an alarm signal, § The CD 4 protein is required to “authenticate” the transaction § Interleukin-1 stimulates helper T-cells to initiate: § Cellular immune response by T cells § Humoral immune response by B cells

T-cells: The Cellular Response § Once activated, the helper T cells secrete interleukin-2 which: § Activates cytotoxic T cells (TC cells) to recognize and destroy cells with the specific antigen found on the antigen-presenting cell § Stimulates proliferation of these activated TC cells § Cytotoxic T cells will also attack transplanted tissue and cause graft rejection § The drug cyclosporin inactivates TC cells

B-cells: The Humoral Response § B cells recognize invading microbes, but do not go on the attack themselves § They produce antibodies that inactivate and mark the pathogen for destruction by non-specific immune defenses § B cells can bind to free and unprocessed antigens § Antigens are endocytosed, processed and presented on the surface with an MHC protein § Helper T cells recognize this complex and stimulate B cells to proliferate into memory cells and plasma cells, which produce antibodies

Mechanisms of Antibody Action § All antibodies form an antigenantibody (immune) complex § Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction

Antibody Diversity § Immune receptor genes are assembled by a process called somatic rearrangement § DNA segments that code for different parts of the receptor molecule are stitched together § Further antibody diversity is generated by: § Imprecise DNA rearrangements § Random mutations § Plasma cells § Produce large amounts of the same antibody that initiated the immune response § B cells can make between one million and one billion different antibody molecules

Antibodies in Blood Transfusions § Blood typing § Rh factor § ABO system is the major group of RBC antigens § The immune system is tolerant to its own antigens § People who are Type A, make antibodies against the B antigen § People who are Type B, make antibodies against the A antigen § People who are Type AB, do not make either anti-A or anti-B antibodies § People who are Type O, make both anti-A and anti. B antibodies § Another group of antigens found on RBCs § Rh-positive people have them; Rh-negative people don’t § Of particular significance when Rh-negative mothers give birth to Rh-positive babies § Mother may be exposed to fetal blood and thus produce anti-Rh antibodies § A subsequent Rh-positive pregnancy leads to erythroblastosis fetalis § Can be prevented by injecting the mother with anti -Rh antibodies

Primary & Secondary Immune Responses § The primary immune response is the first encounter with a foreign antigen § Only a few B cells or T cells can recognize the antigen § Binding of an antigen to its receptor on the lymphocyte stimulates cell division § A clone is produced § This process is called Clonal selection § Memory B cells Circulate blood and lymph, waiting for future exposure § Secondary immune response is faster and amplified about a millionfold

Types of Acquired Immunity § Immunity comes in two forms § Active: where the organism has their own “educated” cells § Passive: where the organism acquires only the antibodies from another source

Summary of How the Immune Response Works Play Immune Response

Supporting Infrastructure Lymphatic system Central location for storage and distribution of immune cells and proteins A network of capillaries, ducts, nodes and organs

Some Invaders Trick the Immune System § Mycobacterium tuberculosis § Resists the cell destroying enzymes and replicates in the macrophages of the lungs § When the immune system finally does respond, the bacterium is protected by a thick waxy wall § HIV (human immunodeficiency virus) § Mimics an antigen presenting cell by activating the macrophage & helper T cells CD 4 receptors § Instead of an antigen it injects its own RNA and 3 enzymes § The immune cells surround the bacterium, walling it off (creating a tubercle) but not killing it § The RNA is transformed into DNA and incorporates with the macrophage or TH cell’s DNA § The bacterium becomes dormant until something acts to weaken the immune system § § At that time it begins to replicate again, causing a new outbreak Play How HIV Infection Works In TH cells, replication destroys the cell and leaves the immune system unable to mount a response to any foreign antigen (AIDS) § A variety of otherwise commonplace infections prove fatal § Death by cancer becomes far more likely

When Profiling Becomes Harassment § Allergies § Body mounts a major defense against a harmless substance § Hay fever § House dust mite § Mast cells initiate the inflammatory response § Release histamine § Capillaries swell mucus production increases § Asthma, histamine causes the narrowing of air passages in the lungs

When the Immune System Makes a Mistake § Autoimmune Diseases § Cytotoxic T cells and B cells lose their ability to distinguish “self” cells from “nonself” cells § The body attacks its own tissues § Examples: § Multiple sclerosis § Type I diabetes § Rheumatoid arthritis § Lupus § Graves’ disease